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Leishmania ( Mundinia ) procaviensis is a parasitic kinetoplastid that was first isolated from a rock hyrax in Namibia in 1975. We present the complete genome sequence of Leishmania ( Mundinia ) procaviensis isolate 253, strain LV425, sequenced using combined short- and long-read technologies. This genome will contribute to our understanding of hyraxes as a Leishmania reservoir.

Supplementary Methods, Supplementary Figures and Figure Legends. Figure S1. EGR1 is a downstream target of BCR and JAK1 signaling (related to Figure 1). Figure S2. Sensitivity of MCL cell lines to EGR1 shRNAs and statistical analysis (related to Figure 2). Figure S3. EGR1 motif analysis and gene set enrichment analysis of RNA-seq data (related to Figure 3). Figure S4. Enrichment of E2F pathway genes in ABC DLBCL after EGR1 knockdown (related to Figure 4). Figure S5. EGR1 regulates expression of MYC and MYC targets and OCI-Ly10 xenografts (related to Figure 4). Figure S6. Enrichment of EGR1 on EGR1 own promoter and EP300 regulatory (5'UTR and enhancer) regions (related to Figure 4). Figure S7. Inhibition of EGR1 transcription and tumor growth by mithramycin (related to Figure 4). Figure S8. Synergism of mithramycin and lenalidomide in ABC DLBCL (related to Figure 6). Figure S9. Expression of MYC and MYC target genes is higher in ABC DLBCL than GCB DLBCL patient samples (related to the Discussion). Figure S10. No correlation between EGR1 and MYC expression in DLBCL cell lines and patient samples (related to the Discussion).

Early growth response gene (EGR1) is a transcription factor known to be a downstream effector of B-cell receptor signaling and Janus kinase 1 (JAK1) signaling in diffuse large B-cell lymphoma (DLBCL). While EGR1 is characterized as a tumor suppressor in leukemia and multiple myeloma, the role of EGR1 in lymphoma is unknown. Here we demonstrate that EGR1 is a potential oncogene that promotes cell proliferation in DLBCL. IHC analysis revealed that EGR1 expression is elevated in DLBCL compared with normal lymphoid tissues and the level of EGR1 expression is higher in activated B cell–like subtype (ABC) than germinal center B cell–like subtype (GCB). EGR1 expression is required for the survival and proliferation of DLBCL cells. Genomic analyses demonstrated that EGR1 upregulates expression of MYC and E2F pathway genes through the CBP/p300/H3K27ac/BRD4 axis while repressing expression of the type I IFN pathway genes by interaction with the corepressor NAB2. Genetic and pharmacologic inhibition of EGR1 synergizes with the BRD4 inhibitor JQ1 or the type I IFN inducer lenalidomide in growth inhibition of ABC DLBCL both in cell cultures and xenograft mouse models. Therefore, targeting oncogenic EGR1 signaling represents a potential new targeted therapeutic strategy in DLBCL, especially for the more aggressive ABC DLBCL.Implications:The study characterizes EGR1 as a potential oncogene that promotes cell proliferation and defines EGR1 as a new molecular target in DLBCL, the most common non-Hodgkin lymphoma.

Supplementary Table S1 including analyzed RNA-seq and ChIP-seq data

International audience; The Surface Water and Ocean Topography (SWOT) mission will vastly expand measurements of global rivers, providing critical new data sets for both gaged and ungaged basins. SWOT discharge products (available approximately 1 year after launch) will provide discharge for all river that reaches wider than 100 m. In this paper, we describe how SWOT discharge produced and archived by the US and French space agencies will be computed from measurements of river water surface elevation, width, and slope and ancillary data, along with expected discharge accuracy. We present for the first time a complete estimate of the SWOT discharge uncertainty budget, with separate terms for random (standard error) and systematic (bias) uncertainty components in river discharge time series. We expect that discharge uncertainty will be less than 30% for two-thirds of global reaches and will be dominated by bias. Separate river discharge estimates will combine both SWOT and in situ data; these “gage-constrained” discharge estimates can be expected to have lower systematic uncertainty. Temporal variations in river discharge time series will be dominated by random error and are expected to be estimated within 15% for nearly all reaches, allowing accurate inference of event flow dynamics globally, including in ungaged basins. We believe this level of accuracy lays the groundwork for SWOT to enable breakthroughs in global hydrologic science.Plain Language Summary The Surface Water and Ocean Topography (SWOT) satellite mission was launched on 15 December 2022. SWOT is designed to produce estimates of river discharge on many rivers where no in situ discharge measurements are currently available. This paper describes how SWOT discharge estimates will be created, and their expected accuracy. SWOT discharge will be estimated using simple flow laws that combine SWOT measurements of river water elevation above sea level, river width, and river slope, with ancillary data such as river bathymetry. We expect that discharge uncertainty will be less than 30% for two-thirds of global reaches and will be dominated by a systematic bias. Temporal variations in river discharge time series are expected to be estimated within 15% for nearly all reaches, thus capturing the response of river discharge to rainfall and snowmelt events, including in basins that are currently ungaged, and providing a new capability for scientists to better track the flows of freshwater water through the Earth system.

Flood events are the most frequent cause of damage to infrastructure compared to any other natural hazard, and global changes (climate, socioeconomic, technological) are likely to increase this damage. Transportation infrastructure systems are responsible for moving people, goods and services, and ensuring connection within and among urban areas. A failed link in these systems can impact the community by threatening evacuation capability, recovery operations and the overall economy. Bridges are critical links in the wider urban system since they are associated with little redundancy and a high (re)construction cost. Riverine bridges are particularly prone to failure during flood events; in fact, the risks to bridges from high river flows and erosion have been recognized as crucial at global level. The interaction of flow, structure and network is complex, and not fully understood. This study aims to establish a rigorous, multiphysics modeling approach for the assessment of the hydrodynamic forces impacting inundated bridges, and the subsequent structural response, while understanding the consequences of such impact on the surrounding network. The objectives of this study are to model hydrodynamic forces as demand on the bridge structure, to advance a performance evaluation of the structure under the modeled loading, and to assess the overall impact at systemic level. The flood-prone city of Carlisle (UK) is used as a case study and a proof of concept. Implications of the hydrodynamic impact on the performance and functionality of the surrounding transport network are discussed. This research will help to fill the gap between current guidance for design and assessment of bridges within the overall transport system.

Current flood risk mapping, relying on historical observations, fails to account for increasing threat under climate change. Incorporating recent developments in inundation modelling, here we show a 26.4% (24.1–29.1%) increase in US flood risk by 2050 due to climate change alone under RCP4.5. Our national depiction of comprehensive and high-resolution flood risk estimates in the United States indicates current average annual losses of US$32.1 billion (US$30.5–33.8 billion) in 2020’s climate, which are borne disproportionately by poorer communities with a proportionally larger White population. The future increase in risk will disproportionately impact Black communities, while remaining concentrated on the Atlantic and Gulf coasts. Furthermore, projected population change (SSP2) could cause flood risk increases that outweigh the impact of climate change fourfold. These results make clear the need for adaptation to flood and emergent climate risks in the United States, with mitigation required to prevent the acceleration of these risks.

Every year flood events lead to thousands of casualties and significant economic damage. Mapping the areas at risk of flooding is critical to reducing these losses, yet until the last few years such information was available for only a handful of well-studied locations. This review surveys recent progress to address this fundamental issue through a novel combination of appropriate physics, efficient numerical algorithms, high-performance computing, new sources of big data, and model automation frameworks. The review describes the fluid mechanics of inundation and the models used to predict it, before going on to consider the developments that have led in the last five years to the creation of the first true fluid mechanics models of flooding over the entire terrestrial land surface.

Disastrous floods have caused millions of fatalities in the twentieth century, tens of billions of dollars of direct economic loss each year and serious disruption to global trade. In this Review, we provide a synthesis of the atmospheric, land surface and socio-economic processes that produce river floods with disastrous consequences. Disastrous floods have often been caused by processes fundamentally different from those of non-disastrous floods, such as unusual but recurring atmospheric circulation patterns or failures of flood defences, which lead to high levels of damage because they are unexpected both by citizens and by flood managers. Past trends in economic flood impacts show widespread increases, mostly driven by economic and population growth. However, the number of fatalities and people affected has decreased since the mid-1990s because of risk reduction measures, such as improved risk awareness and structural flood defences. Disastrous flooding is projected to increase in many regions, particularly in Asia and Africa, owing to climate and socio-economic changes, although substantial uncertainties remain. Assessing the risk of disastrous river floods requires a deeper understanding of their distinct causes. Transdisciplinary research is needed to understand the potential for surprise in flood risk systems better and to operationalize risk management concepts that account for limited knowledge and unexpected developments. River floods have direct and indirect consequences for society, and can cause fatalities, displacement and economic loss. This Review examines the physical and socioeconomic causes and impacts of disastrous river flooding, and past and projected trends in their occurrence.

We present a transparent and validated climate-conditioned catastrophe flood model for the UK, that simulates pluvial, fluvial and coastal flood risks at 1 arcsec spatial resolution (∼ 20–25 m). Hazard layers for 10 different return periods are produced over the whole UK for historic, 2020, 2030, 2050 and 2070 conditions using the UK Climate Projections 2018 (UKCP18) climate simulations. From these, monetary losses are computed for five specific global warming levels above pre-industrial values (0.6, 1.1, 1.8, 2.5 and 3.3 ∘C). The analysis contains a greater level of detail and nuance compared to previous work, and represents our current best understanding of the UK's changing flood risk landscape. Validation against historical national return period flood maps yielded critical success index values of 0.65 and 0.76 for England and Wales, respectively, and maximum water levels for the Carlisle 2005 flood were replicated to a root mean square error (RMSE) of 0.41 m without calibration. This level of skill is similar to local modelling with site-specific data. Expected annual damage in 2020 was GBP 730 million, which compares favourably to the observed value of GBP 714 million reported by the Association of British Insurers. Previous UK flood loss estimates based on government data are ∼ 3× higher, and lie well outside our modelled loss distribution, which is plausibly centred on the observations. We estimate that UK 1 % annual probability flood losses were ∼ 6 % greater for the average climate conditions of 2020 (∼ 1.1 ∘C of warming) compared to those of 1990 (∼ 0.6 ∘C of warming), and this increase can be kept to around ∼ 8 % if all countries' COP26 2030 carbon emission reduction pledges and “net zero” commitments are implemented in full. Implementing only the COP26 pledges increases UK 1 % annual probability flood losses by 23 % above average 1990 values, and potentially 37 % in a “worst case” scenario where carbon reduction targets are missed and climate sensitivity is high.

Leishmania (Mundinia) orientalis is a human pathogen causing leishmaniasis and studies on the properties of metacyclic promastigotes, the parasite’s infective stage, are required for a better understanding of its transmission and infection. However, information on cultivation for mass production of L. orientalis metacyclic promastigotes and factors that stimulate their metacyclogenesis is limited. Therefore, the objective of this study was to develop a suitable methodology for generating promastigote cultures containing a high proportion and number of L. orientalis metacyclic promastigotes. Various media, i.e., Schneider’s insect medium, Medium 199 and Grace’s insect medium, supplemented with various quantities of dithiothreitol, Basal Medium Eagle vitamins, pooled human urine, and fetal bovine serum, were optimized for metacyclogenesis. The results revealed that the optimum culture medium and conditions of those tested were Schneider’s insect medium supplemented with 100 μM dithiothreitol, 1% (v/v) Basal Medium Eagle vitamins, 2% (v/v) pooled human urine, and 10% (v/v) fetal bovine serum, pH 5.0 at 26°C. We also demonstrated that L. orientalis metacyclic promastigotes could be purified and enriched by negative selection using peanut lectin. Under these culture conditions, the highest yield of metacyclic promastigotes was obtained with a significantly higher percentage of parasite survival, resistance to complement-mediated lysis, and infection index in THP-1 macrophage cells compared to parasites cultured without media supplements at neutral pH. This is the first report providing a reliable method for mass production of L. orientalis metacyclic promastigotes for in vivo infections and other experimental studies of this emerging parasite in the future.

This work focuses on the analysis of pilots’ performance during manual flight operations in different stages of training and their influence on gaze strategy. The secure and safe operation of air traffic is highly dependent on the individual performances of the pilots. Before becoming a pilot, he/she has to acquire a broad set of skills by training to pass all the necessary qualification and licensing standards. A basic skill for every pilot is manual control operations, which is a closed-loop control process with several cross-coupled variables. Even with increased automation in the cockpit, the manual control operations are essential for every pilot as a last resort in the event of automation failure. A key element in the analysis of manual flight operations is the development over time in relation to performance and visual perception. An experiment with 28 participants (including 11 certified pilots) was conducted in a Boeing 737 simulator. For defined flight phases, the dynamic time warping method was applied to evaluate the performance for selected criteria, and eye-tracking methodology was utilized to analyze the gaze-pattern development. The manipulation of workload and individual experience influences the performance and the gaze pattern at the same time. Findings suggest that the increase of workload has an increased influence on pilots depending on the flight phase. Gaze patterns from experienced pilots provide insights into the training requirements of both novices and experts. The connection between workload, performance and gaze pattern is complex and needs to be analyzed under as many differing conditions. The results imply the necessity to evaluate manual flight operations with respect to more flight phases and a detailed selection of performance indications.

Underlying higher order chromatin organization are Structural Maintenance of Chromosomes (SMC) complexes, large protein rings that entrap DNA. The molecular mechanism by which SMC complexes organize chromatin is as yet incompletely understood. Two prominent models posit that SMC complexes actively extrude DNA loops (loop extrusion), or that they sequentially entrap two DNAs that come into proximity by Brownian motion (diffusion capture). To explore the implications of these two mechanisms, we perform biophysical simulations of a 3.76 Mb-long chromatin chain, the size of the long Schizosaccharomyces pombe chromosome I left arm. On it, the SMC complex condensin is modeled to perform loop extrusion or diffusion capture. We then compare computational to experimental observations of mitotic chromosome formation. Both loop extrusion and diffusion capture can result in native-like contact probability distributions. In addition, the diffusion capture model more readily recapitulates mitotic chromosome axis shortening and chromatin compaction. Diffusion capture can also explain why mitotic chromatin shows reduced, as well as more anisotropic, movements, features that lack support from loop extrusion. The condensin distribution within mitotic chromosomes, visualized by stochastic optical reconstruction microscopy (STORM), shows clustering predicted from diffusion capture. Our results inform the evaluation of current models of mitotic chromosome formation.

Is there any association detectable between communication and trust in the aviation maintenance sector? Effective communication can have a positive contribution to safety in the aviation maintenanc...

This study investigates the views of Australian Air Traffic Controllers (ATCOs) on increasing levels of automation in Air Traffic Managements Systems (ATMS). An online survey of current and former Australian ATCOs was conducted to identify what tools are considered useful and to what extent automation should be used within ATMS, as well as how increasing automation is expected to impact ATCOs situational awareness. The results highlighted that automation tools that supported and assisted the controller were more likely to be accepted by ATCOs. Automation tools that assumed/replaced the decision making and authority of the ATCO, had lower levels of acceptance by controllers. Increased automation (electronic strips) was considered to have both a positive and negative effect on ATCO situational awareness dependant on the type of role performed by the controller. When transitioning to systems with increased automation, the lack of system understanding/training, skill degradation and the changing role of controllers were considered the three biggest safety risks. By considering this research, the aviation industry can focus on the introduction of automation tools that can best assist ATCOs. Additionally, this study provides invaluable research from ATCOs to inform Air Navigation Service Providers (ANSPs) when implementing more automated ATMS Refereed/Peer-reviewed

The regionalised characteristics of a sub-basin's long-term hydrological behaviour are used as multiple constraint filters for constraining hydrological model simulations in the Congo Basin using the monthly time step Pitman model. The results suggest that the constraints are appropriate in many sub-basins (≥ 20 gauging stations), but not all. Detailed examination of these results suggested that the effects of high slopes (> 7%) could increase the runoff ratio and Q90/MMQ (low flow index) constraint values and that implementing an adjustment factor based on slope did improve some of the very poor results. The percentage points on the FDC falling within the simulated uncertainty band has increased from 0% to 59.6% and 2.4% to 39.9% for the Rift valley and Batéké plateaux regions, respectively. Future studies ideally need a range of different rainfall products to quantify the uncertainties related to the inappropriateness of the CRU rainfall data in some parts of the Congo Basin.

Coleoid cephalopods (squid, cuttlefish, octopus) have the largest nervous system among invertebrates that together with many lineage-specific morphological traits enables complex behaviors. The genomic basis underlying these innovations remains unknown. Using comparative and functional genomics in the model squid Euprymna scolopes, we reveal the unique genomic, topological, and regulatory organization of cephalopod genomes. We show that coleoid cephalopod genomes have been extensively restructured compared to other animals, leading to the emergence of hundreds of tightly linked and evolutionary unique gene clusters (microsyntenies). Such novel microsyntenies correspond to topological compartments with a distinct regulatory structure and contribute to complex expression patterns. In particular, we identify a set of microsyntenies associated with cephalopod innovations (MACIs) broadly enriched in cephalopod nervous system expression. We posit that the emergence of MACIs was instrumental to cephalopod nervous system evolution and propose that microsyntenic profiling will be central to understanding cephalopod innovations.

Animal genomes are organized into chromosomes that are remarkably conserved in their gene content, forming distinct evolutionary units (macrosynteny). We developed a novel three-dimensional chromosomal modelling approach to show that syntenic signals are reflected in conserved three-dimensional networks, encompassed within interaction spheres. We show evidence for evolutionary constraints that could not be surmised by genomic sequence alone, thereby underlining the importance of three-, rather than just two-, dimensional organization.

We present the results for CAPRI Round 50, the fourth joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of twelve targets, including six dimers, three trimers, and three higher-order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interfaces (of the higher-order oligomers). Eight were difficult targets for which only distantly related templates were found for the individual subunits. Twenty-five CAPRI groups including eight automatic servers submitted ~1250 models per target. Twenty groups including six servers participated in the CAPRI scoring challenge submitted ~190 models per target. The accuracy of the predicted models was evaluated using the classical CAPRI criteria. The prediction performance was measured by a weighted scoring scheme that takes into account the number of models of acceptable quality or higher submitted by each group as part of their five top-ranking models. Compared to the previous CASP-CAPRI challenge, top performing groups submitted such models for a larger fraction (70–75%) of the targets in this Round, but fewer of these models were of high accuracy. Scorer groups achieved stronger performance with more groups submitting correct models for 70–80% of the targets or achieving high accuracy predictions. Servers performed less well in general, except for the MDOCKPP and LZERD servers, who performed on par with human groups. In addition to these results, major advances in methodology are discussed, providing an informative overview of where the prediction of protein assemblies currently stands., Cancer Research UK, Grant/Award Number: FC001003; Changzhou Science and Technology Bureau, Grant/Award Number: CE20200503; Department of Energy and Climate Change, Grant/Award Numbers: DE-AR001213, DE-SC0020400, DE-SC0021303; H2020 European Institute of Innovation and Technology, Grant/Award Numbers: 675728, 777536, 823830; Institut national de recherche en informatique et en automatique (INRIA), Grant/Award Number: Cordi-S; Lietuvos Mokslo Taryba, Grant/Award Numbers: S-MIP-17-60, S-MIP-21-35; Medical Research Council, Grant/Award Number: FC001003; Japan Society for the Promotion of Science KAKENHI, Grant/Award Number: JP19J00950; Ministerio de Ciencia e Innovación, Grant/Award Number: PID2019-110167RB-I00; Narodowe Centrum Nauki, Grant/Award Numbers: UMO-2017/25/B/ST4/01026, UMO-2017/26/M/ST4/00044, UMO-2017/27/B/ST4/00926; National Institute of General Medical Sciences, Grant/Award Numbers: R21GM127952, R35GM118078, RM1135136, T32GM132024; National Institutes of Health, Grant/Award Numbers: R01GM074255, R01GM078221, R01GM093123, R01GM109980, R01GM133840, R01GN123055, R01HL142301, R35GM124952, R35GM136409; National Natural Science Foundation of China, Grant/Award Number: 81603152; National Science Foundation, Grant/Award Numbers: AF1645512, CCF1943008, CMMI1825941, DBI1759277, DBI1759934, DBI1917263, DBI20036350, IIS1763246, MCB1925643; NWO, Grant/Award Number: TOP-PUNT 718.015.001; Wellcome Trust, Grant/Award Number: FC001003

Cancers, such as squamous cell carcinoma, frequently invade as multicellular units. However, these invading units can be organised in a variety of ways, ranging from thin discontinuous strands to thick ‘pushing’ collectives. Here we employ an integrated experimental and computational approach to identify the factors that determine the mode of collective cancer cell invasion. We find that matrix proteolysis is linked to the formation of wide strands but has little effect on the maximum extent of invasion. Cell-cell junctions also favour wide strands, but our analysis also reveals a requirement for cell-cell junctions for efficient invasion in response to uniform directional cues. Unexpectedly, the ability to generate wide invasive strands is coupled to the ability to grow effectively when surrounded by extracellular matrix in three-dimensional assays. Combinatorial perturbation of both matrix proteolysis and cell-cell adhesion demonstrates that the most aggressive cancer behaviour, both in terms of invasion and growth, is achieved at high levels of cell-cell adhesion and high levels of proteolysis. Contrary to expectation, cells with canonical mesenchymal traits – no cell-cell junctions and high proteolysis – exhibit reduced growth and lymph node metastasis. Thus, we conclude that the ability of squamous cell carcinoma cells to invade effectively is also linked to their ability to generate space for proliferation in confined contexts. These data provide an explanation for the apparent advantage of retaining cell-cell junctions in squamous cell carcinomas.

Lutzomyia longipalpis is known as one of the primary insect vectors of visceral leishmaniasis. For such ectothermic organisms, the ambient temperature is a critical life factor. However, the impact of temperature has been ignored in many induced-stress situations of the vector life. Therefore, this study explored the interaction of Lu. longipalpis with temperature by evaluating its behaviour across a thermal gradient, thermographic recordings during blood-feeding on mice, and the gene expression of heat shock proteins (HSP) when insects were exposed to extreme temperature or infected. The results showed that 72 h after blood ingestion, Lu. longipalpis became less active and preferred relatively low temperatures. However, at later stages of blood digestion, females increased their activity and remained at higher temperatures. Real-time imaging showed that the body temperature of females can adjust rapidly to the host and remain constant until the end of blood-feeding. Insects also increased the expression of HSP90(83) during blood-feeding. Our findings suggest that Lu. longipalpis interacts with temperature by using its behaviour to avoid temperature-induced physiological damage during the gonotrophic cycle. However, the expression of certain HSP might be triggered to mitigate thermal stress in situations where a behavioural response is not the best option.

Porcisia hertigi is a parasitic kinetoplastid first isolated from porcupines ( Coendou rothschildi ) in central Panama in 1965. We present the complete genome sequence of P. hertigi , isolate C119, strain LV43, sequenced using combined short- and long-read technologies. This complete genome sequence will contribute to our knowledge of the parasitic genus Porcisia .

Leishmania ( Mundinia ) sp. Ghana is a kinetoplastid parasite isolated in 2015 in Ghana. We report the complete genome sequence of L. ( M. ) sp. Ghana, sequenced using combined short-read and long-read technologies. This will facilitate greater understanding of this novel pathogen and its relationships within the subgenus Mundinia .

Geodetic altimeters provide unique observations of the river surface longitudinal profile due to their long repeat periods and densely spaced ground tracks. This information is valuable for calibrating hydraulic model parameters, and thus, for producing reliable simulations of water level for flood forecasting and river management, particularly in poorly instrumented catchments. In this study, we present an efficient calibration approach for hydraulic models based on a steady-state hydraulic solver and CryoSat-2 observations. In order to ensure that only coherent forcing/observation pairs are considered in the calibration, we first propose an outlier filtering approach for CryoSat-2 observations in data-scarce regions using a simulated runoff produced by a hydrologic model. In the hydraulic calibration, a steady-state solver computes the water surface elevation (WSE) profile along the river for selected discharges corresponding to the days of CryoSat-2 overpass. In synthetic calibration experiments, the global search algorithm generally recovers the true parameter values in portions of the river where observations are available, illustrating the benefit of dense spatial sampling from geodetic altimetry. The most sensitive parameters are the bed elevations. In calibration experiments with real CryoSat-2 data, validation performance against both Sentinel-3 WSE and in situ records is similar to previous studies, with Root Mean Square Deviation ranging from 0.43 to 1.14 m against Sentinel-3 and from 0.60 to 0.73 against in situ WSE observations. Performance remains similar when transferring parameters to a one-dimensional hydrodynamic model. Because the approach is computationally efficient, model parameters can be inverted at high spatial resolution to fully exploit the information contained in geodetic CryoSat-2 altimetry.

Leishmania (Mundinia) enriettii is a parasitic kinetoplastid first isolated from a guinea pig in Brazil in 1946. We present the complete genome sequence of L. ( M. ) enriettii isolate CUR178 strain LV763, sequenced using combined short-read and long-read technologies. This will facilitate a greater understanding of the genome diversity within L. ( M. ) enriettii .

Leishmania (Mundinia) orientalis is a kinetoplastid parasite first isolated in 2014 in Thailand. We report the complete genome sequence of L. ( M. ) orientalis , sequenced using combined short-read and long-read technologies. This will facilitate greater understanding of this novel pathogen and its relationship to other members of the subgenus Mundinia .

We provide the raw and processed data produced during the genome sequencing of isolates from six species of parasites from the sub-family Leishmaniinae: Leishmania martiniquensis (Thailand), Leishmania orientalis (Thailand), Leishmania enriettii (Brazil), Leishmania sp. Ghana, Leishmania sp. Namibia and Porcisia hertigi (Panama). De novo assembly was performed using Nanopore long reads to construct chromosome backbone scaffolds. We then corrected erroneous base calling by mapping short Illumina paired-end reads onto the initial assembly. Data has been deposited at NCBI as follows: raw sequencing output in the Sequence Read Archive, finished genomes in GenBank, and ancillary data in BioSample and BioProject. Derived data such as quality scoring, SAM files, genome annotations and repeat sequence lists have been deposited in Lancaster University’s electronic data archive with DOIs provided for each item. Our coding workflow has been deposited in GitHub and Zenodo repositories. This data constitutes a resource for the comparative genomics of parasites and for further applications in general and clinical parasitology., Measurement(s)DNA • genome • sequence_assembly • sequence feature annotationTechnology Type(s)DNA sequencing • Oxford Nanopore Sequencing • Illumina sequencing • sequence assembly process • sequence annotationSample Characteristic - OrganismLeishmaniinaeSample Characteristic - LocationNamibia • Thailand • Ghana • Brazil Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.15134085

Management for high-risk neuroblastoma (NBL) has included autologous hematopoietic stem cell transplant (HSCT) and anti-GD2 immunotherapy, but survival remains around 50%. The aim of this study was to determine if allogeneic HSCT could serve as a platform for inducing a graft-versus-tumor (GVT) effect against NBL with combination immunocytokine and NK cells in a murine model. Lethally irradiated C57BL/6 (B6) x A/J recipients were transplanted with B6 bone marrow on Day +0. On day +10, allogeneic HSCT recipients were challenged with NXS2, a GD2+NBL. On days +14-16, mice were treated with the anti-GD2 immunocytokine hu14.18-IL2. In select groups, hu14.18-IL2 was combined with infusions of B6 NK cells activated with IL-15/IL-15Rα and CD137Lex vivo. Allogeneic HSCT alone was insufficient to control NXS2 tumor growth, but the addition of hu14.18-IL2 controlled tumor growth and improved survival. Adoptive transfer ofex vivoCD137L/IL-15/IL-15Rα activated NK cells with or without hu14.18-IL2 exacerbated lethality. CD137L/IL-15/IL-15Rα activated NK cells showed enhanced cytotoxicity and produced high levels of TNF-αin vitro, but induced cytokine release syndrome (CRS)in vivo. Infusing Perforin-/-CD137L/IL-15/IL-15Rα activated NK cells had no impact on GVT, whereas TNF-α-/-CD137L/IL-15/IL-15Rα activated NK cells improved GVT by decreasing peripheral effector cell subsets while preserving tumor-infiltrating lymphocytes. Depletion of Ly49H+NK cells also improved GVT. Using allogeneic HSCT for NBL is a viable platform for immunocytokines andex vivoactivated NK cell infusions, but must be balanced with induction of CRS. Regulation of TNFα or activating NK subsets may be needed to improve GVT effects.

Landscape evolution models (LEMs) have the capability to characterize key aspects of geomorphological and hydrological processes. However, their usefulness is hindered by model equifinality and paucity of available calibration data. Estimating uncertainty in the parameter space and resultant model predictions is rarely achieved as this is computationally intensive and the uncertainties inherent in the observed data are large. Therefore, a limits-of-acceptability (LoA) uncertainty analysis approach was adopted in this study to assess the value of uncertain hydrological and geomorphic data. These were used to constrain simulations of catchment responses and to explore the parameter uncertainty in model predictions. We applied this approach to the River Derwent and Cocker catchments in the UK using a LEM CAESAR-Lisflood. Results show that the model was generally able to produce behavioural simulations within the uncertainty limits of the streamflow. Reliability metrics ranged from 24.4% to 41.2% and captured the high-magnitude low-frequency sediment events. Since different sets of behavioural simulations were found across different parts of the catchment, evaluating LEM performance, in quantifying and assessing both at-a-point behaviour and spatial catchment response, remains a challenge. Our results show that evaluating LEMs within uncertainty analyses framework while taking into account the varying quality of different observations constrains behavioural simulations and parameter distributions and is a step towards a full-ensemble uncertainty evaluation of such models. We believe that this approach will have benefits for reflecting uncertainties in flooding events where channel morphological changes are occurring and various diverse (and yet often sparse) data have been collected over such events.

Mesenchymal stromal cells (MSCs) are being tested as a cell therapy in clinical trials for dozens of inflammatory disorders, with varying levels of efficacy reported. Suitable and robust preclinical animal models for testing the safety and efficacy of different types of MSC products before use in clinical trials are rare. We here introduce two highly robust animal models of immune pathology: 1) acute radiation syndrome (ARS) and 2) graft versus host disease (GvHD), in conjunction with studying the immunomodulatory effect of well-characterized Interferon gamma (IFNγ) primed bone marrow derived MSCs. The animal model of ARS is based on clinical grade dosimetry precision and bioluminescence imaging. We found that allogeneic MSCs exhibit lower persistence in naïve compared to irradiated animals, and that intraperitoneal infusion of IFNγ prelicensed allogeneic MSCs protected animals from radiation induced lethality by day 30. In direct comparison, we also investigated the effect of IFNγ prelicensed allogeneic MSCs in modulating acute GvHD in an animal model of MHC major mismatched bone marrow transplantation. Infusion of IFNγ prelicensed allogeneic MSCs failed to mitigate acute GvHD. Altogether our results demonstrate that infused IFNγ prelicensed allogeneic MSCs protect against lethality from ARS, but not GvHD, thus providing important insights on the dichotomy of IFNγ prelicensed allogenic MSCs in well characterized and robust animal models of acute tissue injury.

We present the LGAAP computational pipeline, which was successfully used to assemble six genomes of the parasite subfamily Leishmaniinae to chromosome-scale completeness from a combination of long- and short-read sequencing data. LGAAP is open source, and we suggest that it may easily be ported for assembly of any genome of comparable size (∼35 Mb).

The formation of specific protein‐protein interactions is often a key to a protein's function. During complex formation, each protein component will undergo a change in the conformational state, for some these changes are relatively small and reside primarily at the sidechain level; however, others may display notable backbone adjustments. One of the classic problems in the protein‐docking field is to be able to a priori predict the extent of such conformational changes. In this work, we investigated three protocols to find the most suitable input structure conformations for cross‐docking, including a robust sampling approach in normal mode space. Counterintuitively, knowledge of the theoretically best combination of normal modes for unbound‐bound transitions does not always lead to the best results. We used a novel spatial partitioning library, Aether Engine (see Supplementary Materials), to efficiently search the conformational states of 56 receptor/ligand pairs, including a recent CAPRI target, in a systematic manner and selected diverse conformations as input to our automated docking server, SwarmDock, a server that allows moderate conformational adjustments during the docking process. In essence, here we present a dynamic cross‐docking protocol, which when benchmarked against the simpler approach of just docking the unbound components shows a 10% uplift in the quality of the top docking pose.

In the setting of radiation-induced trauma, exposure to high levels of radiation can cause an acute radiation syndrome (ARS) causing bone marrow (BM) failure, leading to life-threatening infections, anemia, and thrombocytopenia. We have previously shown that human macrophages educated with human mesenchymal stem cells (MSCs) by coculture can significantly enhance survival of mice exposed to lethal irradiation. In this study, we investigated whether exosomes isolated from MSCs could replace direct coculture with MSCs to generate exosome educated macrophages (EEMs). Functionally unique phenotypes were observed by educating macrophages with exosomes from MSCs (EEMs) primed with bacterial lipopolysaccharide (LPS) at different concentrations (LPS-low EEMs or LPS-high EEMs). LPS-high EEMs were significantly more effective than uneducated macrophages, MSCs, EEMs, or LPS-low EEMs in extending survival after lethal ARS in vivo. Moreover, LPS-high EEMs significantly reduced clinical signs of radiation injury and restored hematopoietic tissue in the BM and spleen as determined by complete blood counts and histology. LPS-high EEMs showed significant increases in gene expression of STAT3, secretion of cytokines like IL-10 and IL-15, and production of growth factors like FLT-3L. LPS-EEMs also showed increased phagocytic activity, which may aid with tissue remodeling. LPS-high EEMs have the potential to be an effective cellular therapy for the management of ARS.

The Surface Water and Ocean Topography (SWOT) satellite mission aims to improve the frequency and accuracy of global observations of river water surface elevations (WSEs) and slopes. As part of the SWOT mission, an airborne analog, AirSWOT, provides spatially-distributed measurements of WSEs for river reaches tens to hundreds of kilometers in length. For the first time, we demonstrate the ability of AirSWOT to consistently measure temporal dynamics in river WSE and slope. We evaluate data from six AirSWOT flights conducted between June 7–22, 2015 along a ~90 km reach of the Tanana River, AK. To validate AirSWOT measurements, we compare AirSWOT WSEs and slopes against an in situ network of 12 pressure transducers (PTs). Assuming error-free in situ data, AirSWOT measurements of river WSEs have an overall root mean square difference (RMSD) of 11.8 cm when averaged over 1 km2 areas while measurements of river surface slope have an RMSD of 1.6 cm/km for reach lengths >5 km. AirSWOT is also capable of recording accurate river WSE changes between flight dates, with an RMSD of 9.8 cm. Regrettably, observed in situ slope changes that transpired between the six flights are well below AirSWOT's accuracy, limiting the evaluation of AirSWOT's ability to capture temporal changes in slope. In addition to validating the direct AirSWOT measurements, we compare discharge values calculated via Manning's equation using AirSWOT WSEs and slopes to discharge values calculated using PT WSEs and slopes. We define or calibrate the remaining discharge parameters using a combination of in situ and remotely sensed observations, and we hold these remaining parameters constant between the two types of calculations to evaluate the impact of using AirSWOT versus the PT observations of WSE and slope. Results indicate that AirSWOT-derived discharge estimates are similar to the PT-derived discharge estimates, with an RMSD of 13.8%. Additionally, 42% of the AirSWOT-based discharge estimates fall within the PT discharge estimates' uncertainty bounds. We conclude that AirSWOT can measure multitemporal variations in river WSE and spatial variations in slope with both high accuracy and spatial sampling, providing a compelling alternative to in situ measurements of regional-scale, spatiotemporal fluvial dynamics.